October 21, 2013. A lower hippocampal volume is associated with higher glutamate levels in unmedicated subjects with schizophrenia, but not healthy controls, reports a new study from Adrienne Lahti and colleagues at the University of Alabama at Birmingham. The findings, published online October 9, 2013, in JAMA Psychiatry, support the idea that elevated hippocampal glutamate levels in this brain region may underlie the volume reductions observed.

Many studies have found reduced volume of the hippocampus in schizophrenia (Adriano et al., 2012). One hypothesis about this change is that NMDA receptor hypofunction on inhibitory neurons produces a disinhibition of postsynaptic pyramidal neurons, leading to elevated glutamate release and neuronal diminishment, perhaps a function of excitotoxicity (see SRF related news story; Lisman et al., 2008).

First author Nina Kraguljac and colleagues examined the link between hippocampal volume and glutamate levels in 27 healthy controls and 27 subjects with schizophrenia who had been unmedicated for at least two weeks. In addition to using structural magnetic resonance imaging (MRI) to examine hippocampal volume, the researchers also employed single-voxel proton magnetic resonance spectroscopy (1H-MRS) to measure neurometabolite levels in the same subjects.

Unlike the anatomical data provided by MRI, 1H-MRS yields relative concentrations of biochemicals that appear as individual peaks on a spectrum. It is not possible to quantify the glutamate peak in isolation, so the researchers measured the cluster of so-called Glx peaks—a combination of glutamate, glutamine, and GABA signals—and used a method that maximizes glutamate’s contribution. They also examined levels of N-acetylaspartate (NAA), a marker of neuronal integrity. Because data acquisition parameters precluded the quantification of absolute metabolite levels, both Glx and NAA levels were normalized to creatine (Cr), a reference metabolite that appears to be unaltered in the hippocampus of schizophrenia patients (Kraguljac et al., 2012).

Using voxel-based morphometry to analyze the MRI data, the researchers observed hippocampal volumetric deficits in schizophrenia that were largest in the dentate gyrus and the area extending posterolaterally to the cornu ammonis and parahippocampal gyrus. Quantification of the 1H-MRS peaks revealed an increase in the Glx/Cr ratio in the hippocampus in the illness, but no difference in NAA/Cr. Glx/Cr and NAA/Cr levels were significantly correlated in control subjects, but not in those with schizophrenia.

Consistent with their original hypothesis, the researchers observed a negative correlation between Glx/Cr and hippocampal volume in schizophrenia subjects, but not healthy controls. “This pattern suggests that hippocampal glutamate activity is associated with improved neuronal function in healthy individuals but is potentially the cause of hippocampal volume reductions in patients with schizophrenia, likely through a neurodegenerative process,” wrote Harvard Medical School’s Dost Öngür in an accompanying editorial.

The findings of elevated Glx in unmedicated schizophrenia subjects are in agreement with some, but not all, studies conducted in other brain areas such as the medial prefrontal cortex and dorsal caudate (see SRF related news story). The findings in medicated subjects are also mixed, but the majority of studies report unchanged hippocampal glutamate levels. This suggests that antipsychotic treatment may normalize glutamate levels, said the authors.

In contrast to the Glx data, no association between NAA/Cr and hippocampal voxel-based morphometry was found in either group. Given that NAA is presumably a marker of neuronal integrity, the researchers expected NAA/Cr levels and hippocampal volume to be correlated; however, given that several other groups have also failed to find an association, the current results are perhaps not surprising.

Kraguljac and colleagues found no difference in hippocampal volume or neurometabolites between subjects who had previously been on antipsychotics and those who had not, or between first-episode and chronic schizophrenia subjects. The researchers also looked at the relationship between the neuroimaging findings and clinical signs of the illness. Symptoms were assessed using the Brief Psychiatric Rating Scale (BPRS), and cognitive function was measured using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). There was no correlation between volume measures and either BPRS or RBANS score, or between the neurometabolite ratios and either clinical scale.

The authors acknowledge that the non-specificity of the Glx measure and the fact that MRS measures total tissue levels of metabolites, not just those found at the synapse, mean that Glx does not necessarily equate to glutamatergic neurotransmission. Nonetheless, they say that their findings are supportive of the theory that “an altered hippocampal glutamate level potentially accounts for the structural deficits in the hippocampus observed in neuroimaging studies.”—Allison A. Curley.